Histiocytic sarcoma is a rare neoplasm characterized by the malignant proliferation of cells that have the mor- phologic and immunophenotypic features of mature tis- sue histiocytes . It is an aggressive neoplasm with poor prognosis, and the mechanism underlying its pathogen- esis is still unknown . Characteristic features of this sarcoma include the appearance of a solitary mass with systemic manifestations such as fever and weight loss.
Histiocytic sarcoma can be diagnosed on the basis of the morphological features of the histiocytic lineage and by excluding the possibility of lymphoma and other poorly differentiated large-cell malignancies . The diagnosis is confirmed if the biopsy results are positive for more than one immunophenotypic marker for mature histiocytic cells (e.g., CD68, lysozyme, CD11c, and CD14) and negative for myeloid markers (e.g., myeloperoxidase, CD33, and CD34), accessory/dendritic cell markers (CD1a, CD21, and CD35), CD30, HMB-45, epithelial membrane antigen, or keratin . Histiocytic sarcomas usually occur in the intestinal tract, skin, and soft tissues ; therefore, diagnosis of these sarcomas by bone marrow biopsy has rarely been reported. We report a case of histiocytic sarcoma diagnosed by bone marrow biopsy just before the patient’s death.
�Case Report∙Diagnostic Hematology�
A Case of Histiocytic Sarcoma Diagnosed by Bone Marrow Biopsy in a Patient Suffering from Fever for 8 Months
Yun Ha Jang, M.D.1
, Chan-Jeong Park, M.D.1
, Joo Ryong Huh, M.D.2
, Seongsoo Jang, M.D.1
, and Hyun Sook Chi, M.D.1
Departments of Laboratory Medicine1and Pathology2, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Korea
Histiocytic sarcoma is a malignant proliferation of cells showing morphologic and immunopheno- typic features similar to those of mature tissue histiocytes and is known for its rapid progression and poor prognosis. We describe a case of histiocytic sarcoma diagnosed by bone marrow biopsy. A 64-yr-old male was admitted for fever and weight loss that persisted for 8 months. The patient died undiagnosed on the 7th hospitalization day. A bone marrow biopsy performed just before the patient’s death revealed diffuse proliferation of large pleomorphic neoplastic cells with large, round to oval nuclei, vesicular chromatin, and abundant foamy cytoplasm. These cells were positive for histiocytic markers, CD68, lysozyme, CD21, and S-100 protein, but negative for B-cell, T/NK-cell, and epithelial cell markers, thus confirming the presence of histiocytic sarcoma. (Korean J Lab Med 2009;29:282-5)
Key Words : Histiocytic sarcoma, Bone marrow biopsy, Immunohistochemistry
Received :January 30, 2009 Manuscript No :KJLM2229 Revision received :June 29, 2009
Accepted :July 10, 2009
Corresponding author :Chan-Jeong Park, M.D.
Department of Laboratory Medicine, Asan Medical Center, 388-1 Pungnap 2-dong, Songpa-gu, Seoul 138-736, Korea Tel : +82-2-3010-4508 Fax : +82-2-478-0884
E-mail : email@example.com 대한진단검사의학회지 제29권 제4호 2009 Korean J Lab Med 2009;29:282-5 DOI 10.3343/kjlm.2009.29.4.282
8개월 동안 발열을 보인 환자에서 골수검사로 진단된 조직구육종 1예
울산대학교 의과대학 진단검사의학교실∙병리학교실
A Histiocytic Sarcoma Case 283
A 64-yr-old man presented with fever of unknown ori- gin (FUO), which persisted for 8 months. The diagnostic tests for FUO performed in the previous hospital did not help determine the cause of the fever; therefore, he re- ceived only symptomatic therapy with drugs such as an- tipyretics and empirical antibiotics for 8 months. Since whole-body positron emission tomography (PET) revealed several high-intensity lesions in the bone, intestine, skin, and soft tissues, multiple bone metastases were suspected.
However, no specific findings were obtained on perform- ing 3 bone biopsies and several lymph-node and soft-tis- sue biopsies. Bone marrow biopsy revealed marked reac- tive plasmacytosis, mild reactive eosinophilia, mild reac- tive histiocytosis, and characteristics of anemia of chronic disease. Despite all these efforts, the cause of fever could not be found. The patient was discharged after being pre- scribed empirical anti-tuberculosis medication.
However, he was rehospitalized for dyspnea about 2
months later. Physical examination only revealed that he had pitting edema of the leg. A complete blood count showed a leukocyte count of 14,300/mL with 1% myelo- cytes, 1% metamyelocytes, 74% neutrophils, 11% lympho- cytes, 9% monocytes, 3% eosinophils, and 1% atypical lym- phocytes. Normoblasts were also seen at a frequency of 1 per 100 WBCs. The hemoglobin was 8.3 g/dL, and the platelet count was 60,000/μL. Serum biochemistry revealed an elevated total bilirubin level of 10.7 mg/dL (reference interval: 0.2-1.2 mg/dL), alkaline phosphatase level of 388 IU/L (reference interval: 40-120 IU/L), and gamma glutamyl transferase level of 201 IU/L (reference interval:
11-63 IU/L). The aspartate aminotransferase (AST), ala- nine aminotransferase (ALT), and lactate dehydrogenase (LD) levels were normal. The total protein level was 6.6 g/dL (reference interval: 6-8 g/dL) and the albumin level, 1.3 g/dL (reference interval: 3.3-5.2 g/dL); serum elec- trophoresis revealed polyclonal gammopathy. The ferritin concentration was 4,252 ng/mL (reference interval: 20- 320 ng/mL). Coagulation tests revealed that the prothrom-
Fig. 1. Morphologic and immunohistochemical features of the peripheral blood and bone marrow specimen. (A) Rouleaux formation in the peripheral blood smear (Wright stain, ×1,000). (B) Biopsy specimen showing high cellularity, diffuse fibrosis, and large pleomorphic neoplastic cells (H&E stain, ×400). (C) Biopsy specimen showing CD31+ (immunohistochemistry, ×400). (D) Biopsy specimen showing CD68+ cells (immunohistochemistry, ×400). (E) Biopsy specimen showing lysozyme-positive cells (immunohistochemistry, ×400). (F) Biopsy specimen showing S100 protein-positive cells (immunohistochemistry, ×400).
A B C
D E F
284 Yun Ha Jang, Chan-Jeong Park, Joo Ryong Huh, et al.
bin time was 19.0 sec (reference interval: 10-13 sec), acti- vated PTT was 50.5 sec (reference interval: 25.0-35.0 sec).
The concentration of fibrinogen was 552 mg/dL (refer- ence interval: 200-400 mg/dL); that of fibrinogen degra- dation product, 40.0 μg/dL (normal: negative); that of D- dimer, 2.00 μg/mL (reference interval: <0.4 μg/mL); and that of antithrombin III, 28% (reference interval: 80-120%).
Direct Coombs test was positive, and blood and urine cul- tures were negative. A chest radiograph revealed increased heart size, diffuse peribronchial infiltration in the middle zone of both the lungs, and prominent interstitial mark- ings in both lungs. Computed tomography of the abdomen and upper pelvis showed the presence of hepatospleno- megaly and multiple osteolytic lesions in the lumbar spine and left acetabulum. Bone marrow biopsy was refused by the patient. He did not respond to a 4-day dexametha-
sone therapy and died because of respiratory failure.
Bone marrow biopsy and liver biopsy were obtained just before his death. Bone marrow aspiration failed because the aspirate contained little or no marrow. The bone mar- row biopsy showed a cellularity of over 95%, diffuse fibro- sis, increased number of sinusoids, and diffuse non-cohe- sive proliferation of large pleomorphic neoplastic cells with large, round to oval nuclei, vesicular chromatin, and abun- dant foamy cytoplasm (Fig. 1). Immunohistochemistry revealed cells that were CD99+, vimentin+, S100+, CD31+, CD68+, lysozyme+, CD21+, CD4+, CD56-, cytokeratin-, SMA-, SMMHC-, and HMB45-(Table 1). Reactive lymphocytes were positive for CD3, CD20, and CD79α. Masson trichrome staining revealed fine collagen fibers, and iron staining revealed increased hemosiderin. Liver biopsy showed non- specific hepatitis, and there was no evidence of malignan- cy. The diagnosis of histiocytic sarcoma was confirmed by the presence of the morphologic and immunohistochem- ical features described above.
The recent WHO classification defined histiocytic sar- coma as a malignant proliferation of cells showing mor- phologic and immunophenotypic features similar to those of mature tissue histiocytes . Histological sections of sarcomas usually show large, round to oval neoplastic cells with abundant cytoplasm. Hemophagocytosis occurs occa- sionally in the neoplastic cells . The immunohistochem- ical profile shows the expression of lysosomal (macro- phage/histiocytic) markers such as CD68 (in 100% cases), lysozyme (in 98% cases), CD11c, CD14 with the absence of myeloid markers (CD33, CD34, and myeolperoxidase), and accessory/dendritic cell markers [1, 3]. Pileri et al.  recom- mended immunostaining for CD68, lysozyme, CD1a, S100 protein, CD21, and CD35 for the differential diagnosis of histiocytic and accessory dendritic cell neoplasms. CD163, a hemoglobin scavenger receptor, has been suggested as a novel diagnostic marker for histiocytic malignancies .
In our case, the bone marrow of the patient was infiltrat- ed with proliferating large pleomorphic neoplastic cells Antibody This case
Yoshida et al.
Park et al.
Paik et al.
Kim et al.
CD68 + + + + +
Lysozyme ± + + + +
CD163 NT ± NT NT NT
CD79α - - NT NT NT
CD20 - - NT NT -
CD21 ± NT NT - NT
CD3 - - NT - -
CD4 ± + NT NT NT
CD13 NT NT NT NT -
CD30 NT NT - - NT
CD31 + NT + NT NT
CD34 NT NT - NT -
LCA NT NT + + NT
CD45RO NT NT + NT -
CD56 - - NT NT NT
CD99 + NT NT NT NT
CD117 NT NT - NT NT
CD138 NT - NT NT NT
S100 protein + - - - +
Desmin NT NT - NT NT
Vimentin + NT NT NT NT
Cytokeratin - - NT NT NT
HMB45 - NT NT - NT
SMMHC - NT NT NT NT
SMA - NT - NT NT
EMA NT - NT - NT
Table 1. Comparison of the immunohistochemical features of histiocytic sarcoma in this case and several other reported cases
Abbreviations: NT, not tested; LCA, leukocyte common antigen; HMB, human melanoma black; SMMHC, smooth muscle myosin heavy chain;
SMA, smooth muscle actin; EMA, epithelial membrane antigen.
that had large, round to oval nuclei, vesicular chromatin, and abundant foamy cytoplasm. These cells were positive for histiocytic markers, CD68, lysozyme, CD21, and S-100 protein, but negative for B-cell, T/NK-cell, and epithe- lial cell markers. Therefore, we could confirm the diag- nosis of histiocytic sarcoma by excluding the possibility of lymphoma, carcinoma, and melanoma.
Histiocytic sarcoma occurs in individuals across a wide age range; it is mostly found in adults (median age, 46 yr) with a predilection for males . In the majority of the cases, it occurs in extranodal sites, most commonly the intesti- nal tract, skin, and soft tissues . The cause or patho- physiology is still unknown, except, possibly, when medi- astinal germ cell tumors are the precursor lesions [3, 6].
In Korea, several cases of histiocytic sarcoma were re- ported. Two cases were diagnosed on the basis of a soli- tary mass in the rectum  and spleen . In one case, the diagnosis was based on the results of bone marrow biopsy . Their immunohistochemical profiles showed the presence of macrophage/histiocyte markers and the absence of myeloid and lymphoid markers (Table 1).
The prognosis of histiocytic sarcoma is poor . Most patients (60-80%) expire due to progressive disease, because they are diagnosed too late [3, 4]. However, some patients with small, localized primary tumors have a more favorable long-term outcome . Some patients have shown more than 10 yr of disease-free survival . With regard to cases in Korea, a patient with histiocytic sarcoma presented with a 2-cm rectal mass and survived for 32 months without re- lapse . A patient with a multinodular splenic mass show- ed 15 months of disease-free survival . In contrast, a patient with disseminated histiocytic sarcoma diagnosed by bone marrow biopsy, died only 5 months after diagnosis .
In our case, a PET scan of the 64-yr-old male patient showed multiple high-density lesions in the bone, intes- tine, skin, and soft tissue. However, there was no evidence of malignant histiocytic proliferation in the bone, soft- tissue, lymph-node, and liver biopsies. The patient suf- fered from FUO and weight loss for 8 months. Perform- ing diagnostic tests for FUO 3 times did not help deter- mine the cause of the fever. He showed no response to
empirical anti-tuberculosis medication and dexametha- sone therapy and died from respiratory failure. The diag- nosis was made posthumously on the basis of a bone mar- row biopsy taken just before his death.
Understanding this exceedingly rare malignancy is highly important in order to diagnose and treat the patient in time.
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